The aim of this program is to further our understanding of the biology of hematopoietic stem cells and apply this knowledge to develop effective strategies for gene therapy. In studies evaluating novel mechanisms that may provide insights into the regulation of the proliferation and differentiation of stem cells, we will investigate: the role of stem cell interactions mediated by the Drosophila developmental gene, Notch, in determining the fate of stem cells (Project I); methods for inhibiting the retinoic acid pathway to achieve stem cell self renewal (Project II); the role of the bcl-2 gene family in maintaining stem cell survival and differentiation of immature hematopoietic cells (Project III); and the role of Max-interacting proteins in regulating stem cell proliferation and differentiation (Project IV). Results of these efforts will be applied in preclinical and clinical studies of the retroviral mediated transduction of hematopoietic stem cells. In studies to improve our ability to transduce stem cells, we will investigate the determinants of retrovirus entry into stem cells (Project V); and, in nonhuman primates, we will systematically evaluate treatments that elicit stem cells optimally susceptible to viral-mediated gene transduction (Project VI). As a model to evaluate current approaches and to incorporate new developments from this and other research programs, we will initiate a clinical trial of gene therapy for treating patients with leukocyte adhesion deficiency disease by introducing a normal CD18 gene into their hematopoietic stem cells (Project VII). Central to the success of these trials are Core programs which will provide human hematopoietic cells, isolate human and murine hematopoietic stem cells, and prepare retrovirus in large quantities for preclinical and clinical studies. By bringing together investigators with a range of expertise related to hematopoiesis and those with expertise in more basic cellular mechanisms, the SCOR program provides the necessary mechanism for generating novel approaches in this research arena.